title: Role of AMP-activated protein kinase in regulating hypoxic survival and proliferation of mesenchymal stem cells.
abstract: OBJECTIVE
  Mesenchymal stem cells (MSCs) are widely used for cell therapy, particularly for the treatment of ischaemic heart disease. Mechanisms underlying control of their metabolism and proliferation capacity, critical elements for their survival and differentiation, have not been fully characterized. AMP-activated protein kinase (AMPK) is a key regulator known to metabolically protect cardiomyocytes against ischaemic injuries and, more generally, to inhibit cell proliferation. We hypothesized that AMPK plays a role in control of MSC metabolism and proliferation.
  
  
  RESULTS
  MSCs isolated from murine bone marrow exclusively expressed the AMPKα1 catalytic subunit. In contrast to cardiomyocytes, a chronic exposure of MSCs to hypoxia failed to induce cell death despite the absence of AMPK activation. This hypoxic tolerance was the consequence of a preference of MSC towards glycolytic metabolism independently of oxygen availability and AMPK signalling. On the other hand, A-769662, a well-characterized AMPK activator, was able to induce a robust and sustained AMPK activation. We showed that A-769662-induced AMPK activation inhibited MSC proliferation. Proliferation was not arrested in MSCs derived from AMPKα1-knockout mice, providing genetic evidence that AMPK is essential for this process. Among AMPK downstream targets proposed to regulate cell proliferation, we showed that neither the p70 ribosomal S6 protein kinase/eukaryotic elongation factor 2-dependent protein synthesis pathway nor p21 was involved, whereas p27 expression was increased by A-769662. Silencing p27 expression partially prevented the A-769662-dependent inhibition of MSC proliferation.
  
  
  CONCLUSIONS
  MSCs resist hypoxia independently of AMPK whereas chronic AMPK activation inhibits MSC proliferation, p27 being involved in this regulation.
authors.affiliation: Pôle de Recherche Cardiovasculaire, Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Avenue Hippocrate, 55, B1.55.05, Brussels B-1200, Belgium.
authors.forename: Carole
authors.initials: C
authors.lastname: de Meester
authors.forename: Aurélie D
authors.initials: AD
authors.lastname: Timmermans
authors.forename: Magali
authors.initials: M
authors.lastname: Balteau
authors.forename: Audrey
authors.initials: A
authors.lastname: Ginion
authors.forename: Véronique
authors.initials: V
authors.lastname: Roelants
authors.forename: Gauthier
authors.initials: G
authors.lastname: Noppe
authors.forename: Paolo E
authors.initials: PE
authors.lastname: Porporato
authors.forename: Pierre
authors.initials: P
authors.lastname: Sonveaux
authors.forename: Benoît
authors.initials: B
authors.lastname: Viollet
authors.forename: Kei
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Olivier
authors.initials: O
authors.lastname: Feron
authors.forename: Sandrine
authors.initials: S
authors.lastname: Horman
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Vanoverschelde
authors.forename: Christophe
authors.initials: C
authors.lastname: Beauloye
authors.forename: Luc
authors.initials: L
authors.lastname: Bertrand
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001713:Biphenyl Compounds; D049109:Cell Proliferation; D002470:Cell Survival; D064987:Cell- and Tissue-Based Therapy; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D054736:Elongation Factor 2 Kinase / Q000378:metabolism; D004789:Enzyme Activation; D006331:Heart Diseases / Q000628:therapy; D000860:Hypoxia / Q000201:enzymology* / Q000503:physiopathology; D007527:Isoenzymes / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000201:enzymology*; D051379:Mice; D063269:Mitochondrial Turnover; D032383:Myocytes, Cardiac / Q000201:enzymology*; D011753:Pyrones; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D013876:Thiophenes; D054462:p21-Activated Kinases / Q000378:metabolism
chemical_list: D001713:Biphenyl Compounds; D007527:Isoenzymes; D011753:Pyrones; D013876:Thiophenes; D050760:Cyclin-Dependent Kinase Inhibitor p27; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D054462:p21-Activated Kinases; D054736:Elongation Factor 2 Kinase; D055372:AMP-Activated Protein Kinases; C512408:4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile
keywords: AMPK; Glycolysis; Hypoxia; Mesenchymal stem cells; Proliferation